9-95508364-TGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr9-95508364-T-TGCCGCCGCCGCC
• rs71366293
• NM_000264.5:c.-15_-4dupGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000264.5(PTCH1):​c.-15_-4dupGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 147,736 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTCH1 NM_000264.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.30
• Publications: 2 publications found

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.-15_-4dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1777_199-1766dupGGCGGCGGCGGC		intron_variant	Intron 1 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.-15_-4dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1777_199-1766dupGGCGGCGGCGGC		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes AF: 0.0000338 AC: 5 AN: 147736 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000157 AC: 16 AN: 1015962 Hom.: 0 Cov.: 30 AF XY: 0.0000166 AC XY: 8 AN XY: 480702

African (AFR) AF: 0.00 AC: 0 AN: 20162

American (AMR) AF: 0.00 AC: 0 AN: 6622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11094

East Asian (EAS) AF: 0.00 AC: 0 AN: 20892

South Asian (SAS) AF: 0.000735 AC: 14 AN: 19038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18176

Middle Eastern (MID) AF: 0.000389 AC: 1 AN: 2568

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 878574

Other (OTH) AF: 0.0000257 AC: 1 AN: 38836

GnomAD4 genome AF: 0.0000338 AC: 5 AN: 147736 Hom.: 0 Cov.: 22 AF XY: 0.0000556 AC XY: 4 AN XY: 71922

African (AFR) AF: 0.00 AC: 0 AN: 40630

American (AMR) AF: 0.00 AC: 0 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4964

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66442

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00 Hom.: 138

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-15_-4dup12 variant is located in the 5 prime untranslated region (5'UTR) of the PTCH1 gene. This variant results from a duplication of 12 nucleotides at nucleotide positions -15 to -4 upstream from the first translated codon. This nucleotide region is well conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. -

PTCH1-related disorder Benign:1

Nov 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71366293; hg19: chr9-98270646;